The mechanisms underlying the negative regulation of self-reactive B cells that arise during antigen-driven B cell responses remain obscure. The project described in this fellowship application centers on understanding the role of the cytokine BAFF in the regulation of DNA-reactive B cells that enter the germinal center B cell response. Through the use of unique transgenic mouse lines, the influence of BAFF on the fate of self-reactive B cells will be determined. The specific aims are: 1) determine whether BAFF expression by follicular helper T cells alters counter-selection of self-reactive germinal center B cells;and 2) determine whether changes in germinal center B cell TACI receptor expression disturb the counter-selection of self-reactive germinal center B cells. These studies will provide fundamental information on the regulation of self-reactive B cells, which are the source of pathogenic antibodies in a variety of autoimmune disorders including Lupus, and will therefore fulfill the mission of the Transfusion Medicine and Cellular Therapeutics program of the NIHLB. PUBLIC HEALTH RELEVANCE: The proposed studies will test whether exposure of activated DNA-reactive B cells to BAFF, a soluble protein produced by a variety of immune system cells, increases the likelihood that such cells will produce pathogenic antibodies. This work will increase understanding of the mechanisms underlying lupus and related autoimmune disorders.